Unstable Atherosclerotic Plaques Research Articles

Adipokine Levels in Men with Coronary Atherosclerosis on the Background of Abdominal Obesity.

Background. Obesity is associated with dyslipidemia, and excess body fat is associated with unfavorable levels of adipokines and markers of inflammation. The goal of research. To study the level of adipokines and markers of inflammation, their associations with unstable atherosclerotic plaques in men with coronary atherosclerosis on the background of abdominal obesity. Materials and methods. The study involved 82 men aged 40–77 years with coronary atherosclerosis after endarterectomy from the coronary arteries. We divided all men into two groups: 37 men (45.1%) with unstable atherosclerotic plaques, and 45 men (54.9%) who had stable plaques. Obesity was established at a BMI of ≥30 kg/m2. The levels of adipokines and markers of inflammation in the blood were determined by multiplex analysis. Results. In patients with obesity and unstable plaques, the levels of C-peptide, TNFa and IL-6 were 1.8, 1.6, and 2.8 times higher, respectively, than in patients with obesity and stable plaques. The chance of having an unstable plaque increases with an increase in TNFa by 49% in obese patients and decreases with an increase in insulin by 3% in non-obese patients. Conclusions. In men with coronary atherosclerosis and obesity, unstable atherosclerotic plaques in the coronary arteries are directly associated with the level of TNF-α.

Carotid atherosclerotic disease: A systematic review of pathogenesis and management.

Carotid stenosis is an important contributor to ischemic stroke risk with resultant significant impact on neurological disability and death in adults and with worldwide implications. Management of carotid stenosis is impacted by whether there are associated symptoms along with the degree of stenosis. Understanding of the pathogenesis of carotid atherosclerosis or stenosis is important in management of carotid stenosis. Atherosclerotic plaque formation is a chronic insidious process with a number of potential contributors to the formation of such a plaque. The definition of atherosclerosis is not simply limited to abnormal deposition of lipid but also includes a chronic, complex, inflammatory process. Molecularly, in atherosclerosis, there is decreasing nitric oxide (NO) bioavailability, activity and/or expression of endothelial NO synthase, or increasing degradation of NO secondary to enhanced superoxide production. These above changes cause endothelial dysfunction leading to formation of foam cell followed by formation on lipid plaque. After lipid plaque formation, stable or unstable atherosclerotic plaque is formed depending on the calcium deposition over the lipid plaque. It continues to be clearly established that carotid intervention for symptomatic high-grade carotid stenosis is best managed with intervention either by carotid endarterectomy or carotid stenting. However, asymptomatic carotid stenosis is the subject of considerable controversy in terms of optimal management. This review of carotid atherosclerosis is an attempt to incorporate the information provided by more recent studies on pathogenesis and management which may help in the decision-making process for optimal management for protection against stroke.

Identification of hub genes and regulatory networks in histologically unstable carotid atherosclerotic plaque by bioinformatics analysis

ObjectiveThis study identified underlying genetic molecules associated with histologically unstable carotid atherosclerotic plaques through bioinformatics analysis that may be potential biomarkers and therapeutic targets.MethodsThree transcriptome datasets (GSE41571, GSE120521 and E-MTAB-2055) and one non-coding RNA dataset (GSE111794) that met histological grouping criteria of unstable plaque were downloaded. The common differentially expressed genes (co-DEGs) of unstable plaques identified from three mRNA datasets were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG). A protein–protein interaction (PPI) network was constructed to present the interaction between co-DEGs and screen out hub genes. MiRNet database and GSE111794 dataset were used to identify the miRNAs targeting hub genes. Associated transcription factors (TFs) and drugs were also predicted. These predicted results were used to construct miRNA/TFs-hub gene and drug-hub gene regulatory networks.ResultsA total of 105 co-DEGs were identified, including 42 up-regulated genes and 63 down-regulated genes, which were mainly enriched in collagen-containing extracellular matrix, focal adhesion, actin filament bundle, chemokine signaling pathway and regulates of actin cytoskeleton. Ten hub genes (up-regulated: HCK, C1QC, CD14, FCER1G, LCP1 and RAC2; down-regulated: TPM1, MYH10, PLS3 and FMOD) were screened. HCK and RAC2 were involved in chemokine signaling pathway, MYH10 and RAC2 were involved in regulation of actin cytoskeleton. We also predicted 12 miRNAs, top5 TFs and 25 drugs targeting hub genes. In the miRNA/TF-hub gene regulatory network, PLS3 was the most connected hub genes and was targeted by six miRNAs and all five screened TFs. In the drug-hub gene regulatory network, HCK was targeted by 20 drugs including 10 inhibitors.ConclusionsWe screened 10 hub genes and predicted miRNAs and TFs targeting them. These molecules may play a crucial role in the progression of histologically unstable carotid plaques and serve as potential biomarkers and therapeutic targets.

Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque.

Atherosclerosis is a disorder in which, in addition to high cholesterol levels, several plasma factors play a significant role in its development. Among these cytokines and molecules are interleukin 6 (IL-6), interleukin 18 (IL-18), tumor necrosis factor α (TNF-α), metalloproteinase 2 (MMP-2), and metalloproteinase 9 (MMP-9), all of which may contribute to the stabilization of atherosclerotic plaque. The purpose of this study was to determine the effect of advanced lipid-lowering therapy on the levels of these determinants by utilizing proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in patients with verified high-risk atherosclerotic plaque. Methods: The study involved patients with dyslipidemia who had the presence of unstable atherosclerotic plaque verified by ultrasonography and who were eligible to begin alirocumab treatment. The levels of IL-6, IL, 18, TNF-α, and MMPs were determined in this group before and after three months of therapy. After treatment, a statistically significant decrease in concentrations of Il-18, Il-6, TNF-α (p < 0.001) and MMP-2 (p < 0.05) was observed. Additionally, we observed that the concentrations of these markers were significantly higher in the group of patients prior to initiating therapy than in the control group. Our study’s results suggest that PCSK-9 inhibitor therapy significantly reduces the concentration of factors influencing the stability of atherosclerotic plaque, which may explain their essential importance in reducing cardiovascular risk in patients receiving this treatment.

Plasma Concentrations of New Biochemical Markers of Atherosclerosis in Patients with Dyslipidemia-A Pilot Study.

Background and Objectives: The process of atherosclerotic plaque formation and its destabilisation is a process in which many proteins and cytokines are involved. Examples of such proteins are osteopontin (OPN), osteoprotegerin (OPG), metalloproteinases (MMPs) and myeloperoxidase (MPO). The aim of our study is to compare the concentrations of the above-mentioned markers in the plasma of patients with the confirmed presence of rupture plaque in comparison with the plasma of healthy people. Materials and Methods: The study included people suffering from dyslipidemia in whom the presence of unstable atherosclerotic plaque was confirmed by ultrasound. The concentrations of OPN, OPG, MPO, metalloproteinase 2 (MMP-2), and metalloproteinase 9 (MMP-9) in the plasma of these people were determined and compared with the concentrations of these proteins in the plasma of healthy people. Results: Levels of MMP-2, MMP-9 (p < 0.001), OPN, and OPG (p < 0.05) were statistically significantly lower in the group of healthy people than in the study group. Differences in MPO concentration were not statistically significant (p = 0.073). Conclusions: In the plasma of people with confirmed presence of rupture plaque, the concentrations of OPN, OPG, and MMPs are higher compared to the group of healthy people, which may suggest the use of these proteins as novel markers of the presence of unstable atherosclerotic plaque.

Assessment of TNF-α expression in unstable atherosclerotic plaques, serum IL-6 and TNF-α levels in patients with acute coronary syndrome and rheumatoid arthritis.

The role of inflammatory cytokines is well researched in acute coronary syndrome (ACS) and rheumatoid arthritis (RA), but not in the presence of both conditions. This study aimed to compare TNF-α expression, serum TNF-α, IL-6, and hs-CRP in ACS patients with RA (n = 46) with ACS patients without RA (n = 49) and healthy controls (n = 50). TNF-α expression was assessed from coronary artery samples, taken during coronary artery bypass surgery. Serum levels TNF-α, IL-6, and hs-CRP were measured 24 and 48h after cardiac surgery. Stronger TNF-α expression was observed in the ACS patients with RA versus the ACS patients without RA, p = 0.001. Serum TNF-α, IL-6, and hs-CRP at the 24thh were significantly elevated in both patient groups and distinguished them from the healthy controls with accuracy ranging from 80 to 99%. At the 48th h, serum TNF-α and IL-6 in the ACS group without RA decreased to those of the healthy controls but remained high in the group with RA. ACS cases with RA could be correctly identified from the levels of IL-6 (AUC = 0.885, 95% CI 0.791 to 0.938) and TNF-α (AUC = 0.852, 95%CI 0.720 to 0.922). Our results suggest that the presence of RA in ACS cases is likely to provoke stronger TNF-α expression on atherosclerotic plaques, aggravate the pro-inflammatory response, and sustain it even after the cardiac stress is lowered. In ACS cases with RA, long-term monitoring and control of TNF-α and IL-6 levels can be a useful preventive strategy.

Dual-modality Imaging of Angiogenesis in Unstable Atherosclerotic Plaques with VEGFR2-Targeted Upconversion Nanoprobes in vivo

AimAngiogenesis plays a major role in atherosclerotic plaque development and instability. Our study aims to develop a novel optical and magnetic resonance (MR) dual-modality molecular imaging probe to early detect unstable plaques in vivo by targeting biomarkers of angiogenesis in murine models of atherosclerosis (AS).MethodsImmunofluorescence and western blot were used to detect the expression of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in activated Human Umbilical Vein Endothelial Cells (HUVECs). After synthesis and identification of novel short peptide VRBP1-targeted VEGFR2, HUVECs were co-cultured with FITC-VRBP1 to test specific affinity of VRBP1. Then VRBP1-UCNPstargeting VEGFR2 were constructed by conjugating VRBP1 to the surface of NaGdF4:Yb,Er@NaGdF4 nanoparticles. The characterization of the nanoparticles was performed by transmission electron microscopy (TEM), distribution of size, hydrodynamic size, zeta potential, absorption spectra, emission spectra, imaging intensity of different concentrations, binding affinity and cytotoxicity of nanoprobes in vitro. The upconversion luminescence (UCL) and MR imaging were performed to identify unstable atherosclerotic plaque in ApoE−/− mice in vivo and ex vivo. Morphological staining was used to verify AS model and angiogenesis, and Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) was used to confirm accumulation of the nanoparticles after imaging.ResultsAfter induced by hypoxia and ox-LDL, the expression of VEGFR2 in activated HUVECs was enhanced. FITC-VRBP1 can specifically bind to the HUVECs. Characterization of the nanoparticles showed that particles size is uniform with a stable structure, specific optical and MR signal, good binding affinity to VEGFR2 and low cytotoxicity. In vivo and ex vivo UCL imaging and quantitative analysis revealed that distinctive optical signal was observed in the regions of left carotid common arteries (LCCAs) of AS group after injection of VRBP1-UCNPs. Higher signal intensity on T1-weighted MR imaging appeared in the LCCA wall of AS group after injection. The results of morphological staining demonstrated angiogenesis in the atherosclerotic plaques, Gd ions in LCCAs, aortic arch and renal arteries bifurcations detected by ICP-AES confirmed accumulation of the nanoparticles in plaque.ConclusionsWe successfully design and synthesize a novel UCNPs using peptide VRBP1 targeting to VEGFR2. In vivo imaging demonstrates that VRBP1-UCNPs can be used to perform optical/MR dual-modality imaging targeting angiogenesis in plaques, which is a promising technique to early detect unstable atherosclerosis.

Comparison of zinc levels in the various biosubstrates of patients with unstable atherosclerotic plaque.

The article describes the content and comparative characteristics of zinc level in the hair, biopsies of carotid atherosclerotic plaques (AP) and serum in patients with carotid atherosclerosis. The highest concentration of zinc is found in hair compared to the AP and serum. Zinc levels is higher in AP than in the serum. It is noteworthy that the level of zinc in biopsies of unstable AP was lower compared to the level of zinc in hair.

BMAL1 modulates smooth muscle cells phenotypic switch towards fibroblast-like cells and stabilizes atherosclerotic plaques by upregulating YAP1

BackgroundIschemic heart diseases and ischemic stroke are closely related to circadian clock and unstable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) can stabilize or destabilize an atherosclerotic lesion through phenotypic switch. BMAL1 is not only an indispensable core component in circadian clock but also an important regulator in atherosclerosis and VSMCs proliferation. However, little is known about the modulation mechanisms of BMAL1 in VSMCs phenotypic switch and atherosclerotic plaque stability. MethodsWe integrated histological analysis of human plaques, in vivo experiments of VSMC-specific Bmal1−/− mice, in vitro experiments, and gene set enrichment analysis (GSEA) of public datasets of human plaques to explore the function of BMAL1 in VSMCs phonotypic switch and plaque stability. FindingsComparing to human unstable plaques, BMAL1 was higher in stable plaques, accompanied by elevated YAP1 and fibroblast maker FSP1 which were positively correlated with BMAL1. In response to Methyl-β-cyclodextrin-cholesterol, oxidized-low-density-lipoprotein and platelet-derived-growth-factor-BB, VSMCs embarked on phenotypic switch and upregulated BMAL, YAP1 and FSP1. Besides, BMAL1 overexpression promoted VSMCs phonotypic switch towards fibroblast-like cells by transcriptionally upregulating the expression of YAP1. BMAL1 or YAP1 knock-down inhibited VSMCs phonotypic switch and downregulated FSP1. Furthermore, VSMC-specific Bmal1−/− mice exhibited VSMCs with lower YAP1 and FSP1 levels, and more vulnerable plaques with less collagen content. In addition, BMAL1 suppressed the migration of VSMCs. The GSEA results of public datasets were consistent with our laboratory findings. InterpretationOur results highlight the importance of BMAL1 as a major regulator in VSMCs phenotypic switch towards fibroblast-like cells which stabilize an atherosclerotic plaque.

Unstable plaques hide in heavily calcified coronary arteries.

The napkin-ring sign (NRS) was accepted as unstable plaques at coronary computed tomography angiography (CCTA). However, the incidence is relatively low. We sought to assess whether the newly defined diamond-attenuation-sign [DAS, defined as a qualitative plaque feature in a mixed plaque (MP) on CCTA cross-section images by the presence of two features: a visual calcification (in the shape of a diamond) accompanied by an annular-shape lower attenuation plaque tissue surrounding the lumen like a ring], could be accurately identified as unstable atherosclerotic plaques. Eight heart transplant recipients (8 male; mean age, 48.5±11.6 years; range, 37-65 years) underwent CCTA exams prior to heart transplant surgery. Segment-based CCTA sections were independently evaluated for various plaque patterns including non-calcified plaque (NCP) with NRS (NCP-NRS), NCP without NRS (NCP-non-NRS), MP with DAS (MP-DAS), MP without DAS sign (MP-non-DAS), and calcified plaque (CP). NCP-NRS plaques in 6.4% (23/358), NCP-non-NRS plaques in 24.0% (86/358), MP-DAS plaques in 18.2% (65/358), MP-non-DAS plaques in 20.1% (72/358), and calcified-plaques in 7.0% (25/358) of all cases. The specificity and positive predictive values of the MP-DAS and NCP-NRS signs to identify unstable plaque features were excellent (97.1% vs. 98.6%, 90.8% vs. 87.0%, respectively). DAS plaques were more frequently seen on CCTA exams than that of NRS (39.3% vs. 13.3%, respectively, P=0.001). The diagnostic performance of MP-DAS to identify unstable coronary lesions was superior compared to NCP-NRS [area under the receiver operating characteristic curve (ROC), 0.756; 95% CI: 0.717-0.791 vs. 0.558; 95% CI: 0.514-0.600, respectively, P<0.001]. Both the DAS and NRS had a high specificity and positive predictive value for the presence of unstable lesions. DAS was a better identification of unstable atherosclerotic plaques in the assessment of plaque-calcification-pattern (PCP).

Plasma Concentrations of Cytokines in Patients with Combined Hyperlipidemia and Atherosclerotic Plaque before Treatment Initiation-A Pilot Study.

Background and Objectives: The formation and destabilization of atherosclerotic plaques is a complex process involving several proteins and cytokines. Interleukin 6 (IL-6), interleukin 18 (IL-18), and tumor necrosis factor (TNF-α) are examples of such cytokines. The goal of our research is to compare the concentrations of the above-mentioned indicators in the plasma of patients with verified high-risk atherosclerotic plaque to the plasma levels of healthy people before lipid lowering therapy. Materials and Methods: Patients with dyslipidemia who had the presence of unstable atherosclerotic plaque verified by ultrasonography were included in the study. The concentrations of IL-6, IL-18 and TNF-α in the plasma of these people were determined and compared with the concentrations of these cytokines in the plasma of the control group. Results: Levels of lipid panel, IL-6 and IL-18 were significantly lower in the group of healthy people than in the study group. Conclusions: The concentrations of IL-6 and IL-18 in the plasma of patients with ruptured plaque are higher than in the plasma of healthy people, suggesting that these cytokines as a panel might be used as new indicators of the presence of unstable atherosclerotic plaque.

Utility of Ceramide Testing in Men with Erectile Dysfunction

ABSTRACT Introduction Erectile dysfunction (ED) is a known precursor and sequelae to diagnosed cardiovascular disease (CVD). ED AUA guidelines recommend evaluating standard CV risk factors including serum lipids and penile doppler to help stratify CV risk, but few patients are referred for further evaluation. Plasma ceramides are metabolic byproducts that are novel predictors of adverse cardiovascular events resulting from unstable atherosclerotic plaque. CVD risk conferred by ceramide levels has been shown to be independent of conventional risk factors such as LDL and hsCRP levels. Thus, Plasma MI-Heart Ceramide is a new test that useful for evaluating shorter term major adverse cardiovascular events (MACE) in the next 1 to 5 years. Objective We sought to evaluate the utility of ceramide levels in ED patients Methods We initiated ceramide testing in all patients with ED in late 2019 (in addition to lipids and Hgba1c). We queried our electronic medical record for ceramide levels and men with a diagnosis of ED. Ceramide levels stratified patients in normal, moderate, high, and very high risk. Twenty eight patients additionally had penile duplex ultrasound (DUS). Left and right peak systolic velocity values were averaged and a value of &amp;lt;25 cm/s was defined as penile arterial insufficiency. Results 245 men with ED and ceramide levels were analyzed. 44% (n=107) were normal, 42% (n=103) were moderate risk, 12% (n=29) were high risk and 2% (n=6) were very high risk. As result of their ceramide and office evaluation, 42% (15/35) of high/very high risk patients were referred for cardiac evaluation. Comparing ceramide scores in men with penile arterial insufficiency (16.7 cm/sec) vs patients without (43.2 cm/sec), we found no significant difference (p=1). Similarly, when comparing DUS results between ceramide risk categories, we found no significant differences (p=1). Conclusions One in 7 men presenting to an ED clinic had a high or very high ceramide risk. DUS results did not correlate with ceramide risk. Patients undergoing DUS (even without arterial insufficiency) may benefit from additional ceramide testing and possible cardiac referral. Further study is warranted to optimize utility of ceramide in men with ED and potentially decrease peri-procedural IPP cardiac morbidity. Disclosure No

Analysis of differential expression of lipid metabolism genes in atherosclerotic plaques in patients with coronary atherosclerosis

Aim. The goal of the study was to analyze the differential expression of lipid metabolism-related genes in the atherosclerotic plaques of different types in patients with coronary atherosclerosis.Material and Methods. The study was performed on the specimens of atherosclerotic plaques in 45–65-year-old patients with coronary atherosclerosis with stable exertional angina functional class II-IV without acute coronary syndrome. Coronary atherosclerosis was verified by coronary angiography. Atherosclerotic plaque tissue was sampled intraoperatively when indicated. Whole-genome sequencing of ribonucleic acid (RNA) was performed using the TruSeq RNA Sample Preparation Kit (Illumina, USA).Results. We analyzed the differences in the expression of 12 genes including LDLR, APOB, PCSK9, LDLRAP1, LIPA, STAP1, ABCA1, APOA1, APOE, LPL, SCARB1, and SREBF2 depending on the type of atherosclerotic plaques. The expression level of APOE gene was eight times higher in unstable atherosclerotic plaques of dystrophic-necrotic type (p &lt; 0.0001). The expression levels of LDLR and APOB genes were eight times higher in stable atherosclerotic plaques (p &lt; 0.0001). We did not find differences in the expression levels of the ABCG5, ABCG8, APOC3, CETP, CLPS, CYP7A1, and PNPLA5 genes.Conclusion. The study showed the differences in the activity of individual metabolism-related genes in the atherosclerotic plaques of different types in patients with coronary atherosclerosis. Obtained data may become the basis for the development of test systems aimed at predicting the development of atherosclerotic process and its complications.

Белок S100A8 в атеросклеротических поражениях у человека

Introduction. In the pathogenesis of atherosclerosis, a change in the content of different proteins in S100 protein family may play an important role in the formation of atherosclerotic lesions in the vascular wall. The aim was to study the content of mononuclear cells expressing protein S100A8 in different types of atherosclerotic lesions secondary to the development of the inflammatory process in the vascular wall during atherogenesis in humans. Materials and methods. Immunohistochemical and morphometric studies were performed on autopsy material (18 cases) obtained from patients who died from acute cardiovascular insufficiency of atherosclerotic etiology. We detected the expression of S100A8 protein in the aortic segments (from the arc, thoracic and abdominal regions), coronary arteries, and arteries of the circle of Willis (40 tissue samples) using a highly sensitive two-stage streptavidin-biotin method. Comparative analysis was subjected to normal areas of arteries, lipid stain, and unstable and stable atherosclerotic plaques. We performed a statistical analysis with the computer program Statistica Version 10. The significance of the differences between the samples studied was determined by the Student’s T-criterion. Results. Intracellular localization of S100A8 protein was found in the intima of unstable atherosclerotic lesions. Its expression was mainly concentrated in the cytoplasm of macrophages. Intracellular production of S100A8 was minimal or absent in normal areas of aorta intima, coronary arteries, a. basilaris, and in the cap of stable atherosclerotic plaques. We detected numerous inflammatory mononuclear cell infiltrates in the areas of the vascular wall with S100A8 expression. According to the morphometry, their content in the intima of unstable plaques significantly exceeded the similar rate in the intima of normal areas of arteries and stable lesions. Conclusion. We hypothesize that protein S100A8 may contribute to the activation of immune-inflammatory reactions in the vascular wall, which are the basis for the formation of unstable progressive atherosclerotic lesions leading to the development of acute coronary syndrome. Further research may provide more evidence to support that S100A8 proteins are a promising drug target in the prevention and therapy of atherosclerosis. Keywords: atherogenesis, S100A8 protein, unstable atherosclerotic plaque

ДИНАМИКА МАРКЕРОВ ФУНКЦИИ ЭНДОТЕЛИЯ, ПРО- И ПРОТИВОВОСПАЛИТЕЛЬНЫХ ЦИТОКИНОВ В ЗАВИСИМОСТИ ОТ ВЫРАЖЕННОСТИ ХРОНИЧЕСКОЙ ДЫХАТЕЛЬНОЙ НЕДОСТАТОЧНОСТИ У ПАЦИЕНТОВ С ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНЬЮ ЛЕГКИХ

The publication is devoted to the study of markers of endothelial function, pro- and anti-inflammatory cytokines in patients with chronic obstructive pulmonary disease depending on the severity of chronic respiratory failure and disorders of arterial blood hemoglobin oxygen saturation. The authors established a decrease in the activity of cellular immunity, insufficient activation of humoral immunity, decrease in antioxidant protection and anti-inflammatory activity of the immune system. Signs of the key link in the development of atherosclerosis – endothelial dysfunction – were revealed in patients with COPD. The results of the study suggest that the degrees of chronic respiratory failure are interrelated with the stages of atherosclerotic process development. Disturbances of hemoglobin saturation of arterial blood with oxygen and pronounced degrees of chronic respiratory failure are considered as factors contributing to the stage of atheromatosis, which underlies the formation of unstable atherosclerotic plaque.

Atherogenic index of plasma: A valuable novel index to distinguish patients with unstable atherogenic plaques.

Background:Plaque instability is a leading cause of morbidity and mortality in coronary artery disease (CAD) patients. Numerous efforts have been made to figure out and manage unstable plaques prior to major cardiovascular events incidence. The current study aims to assess the values of the atherogenic index of plasma (AIP) to detect unstable plaques.Materials and Methods:The current case-control study was conducted on 435 patients who underwent percutaneous coronary intervention due to chronic stable angina (stable plaques, n = 145) or acute coronary syndrome (unstable plaques, n = 290). The demographic, comorbidities, chronic medications, biochemical and hematological characteristics of the patients were entered into the study checklist. The baseline AIP was measured according to the formula of triglycerides/high-density lipoprotein logarithm. Binary logistic regression was applied to investigate the standalone association of AIP with plaque instability. Receiver operating curve (ROC) was depicted to determine a cut-off, specificity, and sensitivity of AIP in unstable plaques diagnosis.Results:AIP was an independent predictor for atherogenic plaque unstability in both crude (odds ratio [OR]: 3.677, 95% confidence interval [CI]: 1.521–8.890; P = 0.004) and full-adjusted models (OR: 15, 95% CI: 2.77–81.157; P = 0.002). According to ROC curve, at cut-point level of 0.62, AIP had sensitivity and specificity of 89.70% and 34% to detect unstable plaques, respectively (area under the curve: 0.648, 95% CI: 0.601–0.692, P < 0.001).Conclusion:According to this study, at the threshold of 0.62, AIP as an independent biomarker associated with plaque instability can be considered a screening tool for patients at increased risk for adverse events due to unstable atherosclerotic plaques.

Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability

BackgroundDiabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture as seen in patients, can be applied to study the effects of diabetes and respective therapeutics on plaque instability/rupture.Methods and ResultsApoE−/− mice at 7 weeks of age were rendered diabetic with streptozotocin and 5 weeks later were surgically subjected to tandem stenosis in the right carotid artery and fed with a high‐fat diet for 7 weeks. As a promising new antidiabetic drug class, a sodium glucose co‐transporter 2 inhibitor was tested in this new model. Diabetic mice showed an increase in the size of unstable atherosclerotic plaques and in the plaque instability markers MCP‐1, CD68, and necrotic core size. Mice treated with dapagliflozin demonstrated attenuated glucose and triglyceride levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap‐to‐lesion height ratios, and significant upregulation of the vasculoprotective NADPH oxidase 4 expression.ConclusionsThe tandem stenosis mouse model in combination with the application of streptozotocin represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque‐stabilizing effects of sodium‐glucose co‐transporter 2 inhibitor. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing antidiabetic drugs for the highly sought‐after potential to stabilize atherosclerotic plaques.

Innovative Approaches to Assess Intermediate Cardiovascular Risk Subjects: A Review From Clinical to Metabolomics Strategies.

Current risk stratification strategies for coronary artery disease (CAD) have low predictive value in asymptomatic subjects classified as intermediate cardiovascular risk. This is relevant because not all coronary events occur in individuals with traditional multiple risk factors. Most importantly, the first manifestation of the disease may be either sudden cardiac death or acute coronary syndrome, after rupture and thrombosis of an unstable non-obstructive atherosclerotic plaque, which was previously silent. The inaccurate stratification using the current models may ultimately subject the individual to excessive or insufficient preventive therapies. A breakthrough in the comprehension of the molecular mechanisms governing the atherosclerosis pathology has driven many researches toward the necessity for a better risk stratification. In this Review, we discuss how metabolomics screening integrated with traditional risk assessments becomes a powerful approach to improve non-invasive CAD subclinical diagnostics. In addition, this Review highlights the findings of metabolomics studies performed by two relevant analytical platforms in current use–mass spectrometry (MS) hyphenated to separation techniques and nuclear magnetic resonance spectroscopy (NMR) –and evaluates critically the challenges for further clinical implementation of metabolomics data. We also discuss the modern understanding of the pathophysiology of atherosclerosis and the limitations of traditional analytical methods. Our aim is to show how discriminant metabolites originated from metabolomics approaches may become promising candidate molecules to aid intermediate risk patient stratification for cardiovascular events and how these tools could successfully meet the demands to translate cardiovascular metabolic biomarkers into clinical settings.

A novel animal model for vulnerable atherosclerotic plaque: dehydrated ethanol lavage in the carotid artery of rabbits fed a Western diet.

The study of unstable atherosclerotic plaques is limited by the absence of ideal animal models to reproduce the plaque instability observed in humans. In this study, we attempted to develop a novel animal model for vulnerable atherosclerotic plaques using dehydrated ethanol lavage in rabbits fed a Western diet (WD). A total of 30 New Zealand White (NZW) rabbits were randomized to 5 groups, including a control group with or without WD, a balloon injury with WD group, and an ethanol injury with or without WD group. Operations were conducted using the right common carotid artery as the target vessel. All animals were followed up for 3 months unless a vascular event occurred. Blood samples and carotid artery specimens were ultimately collected for analysis of atherogenesis. Compared to rabbits in which lesions were induced by balloon injury, those subjected to an ethanol lavage with high cholesterol diet showed progressive atherosclerotic lesions in all carotid artery segments, which were characterized by greater plaque burden, smaller minimum lumen area (MLA), and increased vulnerability as indicated by abundant macrophages, scattered smooth muscle cell (SMC) composition, higher matrix metalloproteinase-9 (MMP-9) expression in plaques, thinner fibrous cap thickness, and higher possibility of stroke event (50% vs. 0%). Meanwhile, the serum interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) levels in the ethanol injury group with a high-cholesterol diet were significantly higher than those in the balloon injury group after 3 months (all P<0.01). We successfully established a novel animal model for vulnerable atherosclerosis by ethanol exposure of the carotid segment that has a higher predictive value for the probability of ischemic events than the balloon injury model. Therefore, it may represent a promising animal model for investigating new therapeutic approaches, novel imaging modalities, and underlying mechanisms for vulnerable atherosclerotic plaque.

Abstract 10227: High-Sensitive Magnetic Particle Imaging of Intraplaque Hemorrhage for Identification of Unstable Atherosclerotic Plaques

Introduction: Intraplaque hemorrhage (IPH), which is believed to arise from immature neovessels, drives atherosclerosis progression and is an imaging predictor of stroke and myocardial infarction. However, detection of IPH using magnetic resonance imaging (MRI) might be limited due to false signals from varied plaque components. Magnetic particle imaging (MPI) is a novel tomographic method that directly images the magnetization of ferromagnetic particles. Aims: To test whether MPI can image IPH for detecting unstable plaques and exploring the mechanism of IPH. Methods: The tandem stenosis (TS) mouse model was used to establish unstable plaques with IPH. The intervention agent used for reducing IPH was 4-ABAH. TS ApoE -/- mice and human carotid endarterectomy samples were scanned with MPI and computed tomography. IPH was confirmed by fat-suppressed T1-weighted MRI and Prussian blue staining. Plaque specimens were analyzed histologically. Results: Human carotid samples exhibited endogenous MPI signals, which were related to IPH. Hemosiderin was likely the source of MPI signals. Seven weeks post-TS, unstable plaques in the right carotid artery showed endogenous MPI signals, which were three-fold greater compared with stable plaques in the brachiocephalic artery or normal arterial wall (P &lt; 0.05). From the temporal points, MPI signals in unstable plaques increased from 3.05 ± 1.45 (4 weeks) to 7.29 ± 4.47 (7 weeks) and reduced to 2.59 ± 0.84 (11 weeks) (P &lt; 0.05), while intraplaque neovessel densities showed no difference. Compared with 4 or 7 weeks post-TS, intraplaque neovessels at 11 weeks revealed a more mature phenotype indicated by increased neovessel lumen areas and VE-cadherin (endothelial junction marker) expressions (P &lt; 0.05). Administered 4-ABAH attenuated MPI signals in unstable plaques (9.38 ± 6.75 vs. 3.11 ± 1.25, P &lt; 0.05) and downregulated vWF (endothelial damage marker) expressions (P &lt; 0.05) without affecting neovessel densities or lumen areas. Conclusions: MPI allows ex vivo IPH imaging in human carotid tissues, in vivo IPH monitoring and unstable plaque detection in ApoE -/- mice. MPI-detected IPH is likely associated with endothelial barrier function. As a result, MPI is a promising method for detecting unstable plaques in patients.